1. Field of the Invention
The present invention relates to the treatment of taupathies and, more particularly, to passive immunization targeting the N-terminal projection domain of tau.
2. Description of the Related Art
Alzheimer's disease (AD) is the most common type of dementia and is characterized by progressive loss of memory and other cognitive functions. The two major histopathological hallmarks in brains of AD patients are extracellular senile plaques consisting of amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs), composed of abnormally hyperphosphorylated tau protein. The tau pathology made up of the hyperphosphorylated tau is also a hallmark of several neurodegenerative disorders, which include frontolobar dementias, the corticobasal degeneration, progressive supranuclear palsy, Pick disease, Guam Parkinsonism dementia complex, and dementia pugilistica. The density of tau lesions directly correlates with dementia.
At present, there is no effective treatment available for AD and related tauopathies. Most therapeutic approaches for AD mainly focused on reducing Aβ levels in the brain which included blocking the formation of Aβ by modulating β-secretase and/or γ-secretase, promoting the clearance of Aβ, preventing aggregation of Aβ and destabilizing Aβ oligomers; however, to date, none of these approaches have yielded a successful outcome. The first tau immunotherapy targeting active immunization against truncated tau, tau 151-391, is now in Phase I human clinical trial.
Harnessing the immune system to prevent or remove the Aβ and tau aggregates is an emerging and promising disease-modifying approach for AD. In the last decade, Aβ immunotherapy progressed from preclinical studies in transgenic mouse models of AD to clinical trials in humans. While immunization with Aβ increased the clearance of Aβ, it failed to reduce neurofibrillary pathology and prevent progressive neurodegeneration. Furthermore, Aβ immunotherapies showed little cognitive benefit in mild-to-moderate AD patients. Importantly, multivariate analyses indicate that neurofibrillary tangles, neuron number loss and synapse loss, but not amyloid load, strongly correlate with cognitive impairment in AD patients. These findings have led to the belief that targeting tau pathology might be more effective than Aβ-directed therapy for AD.
Intracellular aggregates of tau locate inside of neuron, which complicates its targeting for clearance. However, active immunization with recombinant α-synuclein in a transgenic mouse model was found to decrease aggregates of α-synuclein, an intracellular synaptic protein that accumulates in the brains of patients with Parkinson's disease and AD. This finding supported that intracellular proteins could also be potential targets for immunotherapy. Indeed, immunotherapy targeting pathological tau has been tested in several AD transgenic mouse models with different phospho-tau peptides. Accumulating evidence from these preclinical studies has shown that active immunization in transgenic tauopathy mouse models using tau phospho-peptides reduce tau pathology and rescue or slow the cognitive decline. Passive immunotherapy using antibodies against pathology of tau has also been shown to slow disease progression.
Tau pathology is believed to spread transcellularly. The abnormally hyperphosphorylated/oligomeric tau released in the extracellular space from the affected neurons is suspected to serve as the seeds for the spread of tau pathology by the ingesting cells. Therefore, tau immunotherapy may clear extracellular tau that is involved in the spreading of tau pathology. One study screened tau antibodies with the ability to block seeding activity present in P301S brain; infusion of tau antibodies specific for blocking P301S tau seeds into the lateral ventricle of P301S mice for 3 months reduced hyperphosphorylated, aggregated and insoluble tau, blocked development of tau seeding activity, and improved cognitive deficits. This finding indicated that tau immunotherapy can target its transcellular propagation.
Tau protein consists of an N-terminal projection region, a proline-rich domain, a microtubule-binding domain, and a C-terminal region. Although the role of tau in regulating microtubule dynamics is extensively established, much less is known about the functional role of the N-terminal domain of tau on neuron survival. A 17-kD N-terminal tau fragment generated by calpain cleavage, comprising residues amino acid 45-230, was proposed to mediate Aβ-induced toxicity, and mediate tau neurotoxicity in Drosophila tauopathy model. However, the toxicity and in vivo relevance of this 17 kD fragment are debated. Garg et al. reported that this 17 kD fragment cleaved by calpain is tau 125-230, which is much shorter than previously reported tau 45-230. Furthermore, both tau 125-230 and tau 45-230 fragments showed no toxicity in Chinese hamster ovary (CHO) cells, neuroblastoma cells (N2a) and in primary hippocampal neurons. Other N-terminal tau fragments including tau 1-44, tau 26-44, tau 26-230 and tau 1-156 were reported to cause an NMDAR-mediated powerful toxicity in cerebellar granule neurons, but tau 45-230 exerted a toxicity with unknown mechanism. Tau 1-230 was also reported to protect neuron from apoptosis, which indicated that N-terminal domain of tau can be either neuroprotective or neurotoxic according to its length. Alzheimer abnormally hyperphosphorylated tau, instead of interacting with tubulin and promoting its assembly into microtubules, sequesters normal tau, forming oligomers and consequently filaments which can be sedimented at 100,000 to 200,000×g.